Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/16815
Title: PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling
Authors: Liu, Y
Lui, ELH
Friedman, SL
Li, L
Ye, T 
Chen, Y
Poon, RT
Wo, J
Kok, TW
Fan, ST
Keywords: Akt
Apoptosis
Cell cycle
Hepatic stellate cell
Liver fibrosis
PTK787/ZK22258
Issue Date: 2009
Publisher: Nature Publishing Group
Source: Laboratory investigation, 2009, v. 89, no. 2, p. 209-221 How to cite?
Journal: Laboratory Investigation 
Abstract: Liver fibrosis due to hepatic stellate cell (HSC) activation represents a common response to chronic liver injury. PTK787/ZK222584 (PTK/ZK) is a pan-VEGFR tyrosine kinase inhibitor. The aim of this study was to examine the effect of PTK/ZK in liver fibrosis. In primary HSCs, PTK/ZK inhibited the expression of α-smooth muscle actin (α-SMA), collagen, tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as cell proliferation, migration and actin filament formation. PTK/ZK-induced apoptosis of HSCs, which was correlated with increased caspase-3 activation and suppressed Bcl-2 expression. PTK/ZK also induced cell cycle arrest, accompanied by increasing the expression of p27 Kip1 and downregulation of cyclin D1 and cyclin E. PTK/ZK significantly inhibited vascular endothelial growth factor (VEGF) expression, as well as VEGF-simulated cell proliferation and phosphorylation of Akt in activated HSCs. In a murine fibrotic liver, PTK/ZK attenuated collagen deposition and α-SMA expression in carbon tetrachloride-induced fibrosis in both a 'prevention' and 'treatment' dosing scheme. These beneficial effects were associated with reduced phosphorylation of Akt and suppressed mRNA expression of procollagen-(I), TIMP-1, matrix metalloproteinase-9 and CD31. These findings provide novel insights into the potential value of blocking VEGF signaling by a small molecule tyrosine kinase inhibitor in treating hepatic fibrosis.
URI: http://hdl.handle.net/10397/16815
DOI: 10.1038/labinvest.2008.127
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